Our objective is to investigate gene-environment interactions in the etiology of colorectal polyps. We are currently conducting a sigmoidoscopy-based case-control study of polyps. Cases are asymptomatic subjects with a first-time diagnosis of adenomatous polyps. Controls have no history of any polyps and screen negative at sigmoidoscopy. Subjects complete a food frequency questionnaire, an interview regarding physical activity, medicines, including NSAID's, and hormones, and provide a fasting blood sample for analyses of serum nutrient levels. The buffy coat has been saved and we have access to all tumor tissue taken at sigmoidoscopy and colonoscopy. There will be 600 cases and 600 controls by the start of this proposed study. We propose to study the effect of selected metabolic genes on risk of polyps and see whether these genes modify the effects of other exposures. We will focus first on acetylator genotypes (NAT2 polymorphism) and NAT1 and cytochrome P-450 (CYP1A2) phenotypes and their possible modification of the red meat effect, and ApoE and its possible modification of lipid-related exposures. We also plan to study the effect of other genes related to lipoproteins (ApoAII, ApoB, ApoI/CIII, AIV cluster, and LDL receptor), guided somewhat by results with ApoE, and to study glutathione S- transferase and its effect on risk of polyps. Also, as part of Project 3, tumor tissue from polyps cases will be studied for somatic events related to K-ras, APC, DCC, MCC and p53, as well as evidence of genomic instability related to the familial colon cancer (FCC) gene on chromosome 2. The same polyps cases will be studied for involvement (germline or somatic) of the FCC gene after it is cloned and characterized. We propose here to investigate gene-environment interactions involving the oncogenes and tumor suppressor genes listed above. Given that our outcome is polyps, we expect to have greater power to study K-ras and FCC since these are likely to be more common events. This is Project 2. Project 1 is a genetic-epidemiologic study of familial colorectal cancer and Project 3 focusses on the molecular genetics of both colorectal cancer and polyps.